tbuckley/cabot-search huggingface dataset:
Abstract 15184: Connective Tissue Disease Subtype and Pregnancy: Risk of Lifelong Thoracic Aortic Aneurysmal Disease
Authors: Afsheen Nasir, Mohammad Zafar, Asanish Kalyanasundaram, Alexandra Sonsino, Dimitra Papanikolaou, Maryam Tanweer, Yupeng Li, Bulat A Ziganshin, robert elder, katherine H campbell, Lawrence S Cohen, John A Elefteriades, Josephine Chou
Journal: Circulation (2022)

Introduction: Pregnancy may increase the risk of thoracic aortic aneurysm (TAA) and its complications in connective tissue disease (CTD) patients, but risk by CTD subtype is unclear. Methods: Using the Yale Aortic Institute database, we identified 244 female patients with Marfan’s, Ehlers Danlos, or Loeys Dietz Syndromes. We included imaging, clinical, surgical and pregnancy information using retrospective chart review. Results: Among MFS patients, 50% were ever-pregnant and had TAA; 20% were ever-pregnant and did NOT have TAA, while 25% were never-pregnant and had TAA. Ever-pregnant MFS had higher rates of Ao dissection (13% vs 7%), Ao surgery (45% vs 20%), and mortality both all cause (11% vs 0) and CV/Ao (5% vs 0).Among EDS patients, only 7% were ever-pregnant and had TAA; 66% were ever-pregnant and did NOT have TAA, while 1% were never-pregnant and had TAA. Overall low rates of Ao dissection (2%), Ao surgery (&gt;1%), and mortality (2% all cause and 0.6% Ao/CV) were seen in ever-pregnant group.LDS population was small. TAA rate and need for Ao surgery were more common in the ever-pregnant group. No dissections or deaths in either group. Conclusion: Ever-pregnant patients with MFS had the highest risk of TAA, Ao dissection, Ao surgery and mortality. In contrast, ever-pregnant EDS patients had low rates of TAA and complications. Ever-pregnant LDS may be more likely to develop TAA and need for Ao surgery.
Abstract 14509: A Rare Case of Cardiac Tamponade as an Initial Presentation of Native Aortic Valve Infective Endocarditis
Authors: Mahati Dasari, Pramukh Arun Kumar, Ayita Ray, Robert Bojar, Ramses Thabet Nasif
Journal: Circulation (2022)

Background: Pericardial involvement is a rare presentation of infectious endocarditis (IE). We present a case of septic cardiac tamponade, paravalvular abscess and fibrinous pericarditis secondary to native aortic valve (AV) IE. Presentation: A 50-year-old gentleman with a history of IV drug use presented with fever, dyspnea and pleuritic chest pain for one week. He was febrile, tachycardic and hypotensive on presentation. Examination revealed a new onset early diastolic murmur. Workup: EKG showed mild diffuse ST segment elevations and PR segment depressions suggestive of pericarditis. Blood cultures grew Serratia marcescens in 6 out of 6 bottles and IV cefepime was initiated. TTE revealed large effusion with right atrium and right ventricle diastolic collapse consistent with tamponade physiology (fig. A, B). A vegetation was seen on the right coronary cusp of AV along with aortic insufficiency and aortic root abscess. TEE confirmed the above findings (fig. C-F) Management: An emergency cardiac surgery was performed for acute aortic regurgitation and cardiac tamponade. Intraoperative findings revealed 600mL of purulent effusion. A large vegetative mass near left-to-right commissure covering an abscess cavity that extended into the aortic wall that destroyed the annulus and extended into the ventricular muscle. AV replacement with 21mm Inspiris pericardial AV and pericardial patching was done. Epicardial tissue as well as AV leaflet cultures revealed moderate to heavy growth of S. marcescens . He was discharged on cefepime for a total duration of 6 weeks. Follow up TTE revealed normal peak and mean transaortic gradients. Conclusion: Cardiac tamponade is a rare but life-threatening complication of IE. Pericardial involvement should prompt us further work up to exclude intra-cardiac abscess which carries poor prognosis due to high complication rates. Hence, early multidisciplinary team response is of paramount importance to reduce in-hospital mortality.
Abstract 15182: Recruiting Super-Relaxed Myosin to Restore Contractility in Human Right Heart Failure
Authors: Vivek Jani, Imran Aslam, Axel Fenwick, Weikang Ma, Henry Gong, Devin Nissen, Ilton M Cubero Salazar, Olivia Hanselman, Arielle Abovich, Monica Mukherjee, Kenneth B Margulies, Anthony Cammarato, Thomas Irving, David A Kass, Steven Hsu
Journal: Circulation (2022)

Intro: Right ventricular (RV) dysfunction worsens outcomes in pulmonary hypertension (PH) due to heart failure with reduced ejection fraction (HF), yet underlying mechanisms are unknown. We previously reported RV myofilament max calcium-activated tension (T max ) is reduced in human PH-HF. Here, we reveal that this decline is due to more myosin heads in the super-relaxed (SRX) state which lack force-production due to low ATP turnover. Methods: Frozen RV myocardium from 25 PH-HF and 9 control patients were permeabilized and myocyte mechanics and small angle X-ray diffraction measured. Results: RV T max (16±4 vs. 23±3 mN/mm 2 , p&lt;1x10 -15 ) and peak power (0.06±0.01 vs. 0.11±0.03, p=7.9x10 -5 ) were 50% lower in HF. Unsupervised machine learning (infinite mixture Dirichlet process) using mechanics identified two HF subgroups distinguished by RV T max : Group 1 with slightly reduced T max (19±1 mN/mm 2 , p=3.8x10 -6 ) and Group 2 with 40% reduced T max (14±3 mN/mm 2 , p&lt;1x10 -15 ), with Group 2 exhibiting clinically overt RV failure vs. Group 1 (right atrial pressure, RAP 14±6 vs. 9±4, p=0.01; RAP/pulmonary capillary wedge ratio 0.7±0.3 vs. 0.4±0.2, p=0.047). To test if low RV T max was associated with more SRX myosin, X-ray diffraction patterns from RV myofibers were used to determine the equatorial intensity ratio (I 1,1 /I 1,0 ), an indicator of myosin proximity to the thick filament backbone. The ratio was lower (more SRX), which was associated with reduced myosin ATP turnover in Group 2 vs. both 1 (p=9.0x10 -7 ) and controls (p=1.8x10 -9 ). We then tested the effect of SRX on T max by perturbing the proportion of SRX myosin using mavacamten (M), a myosin inhibitor that stabilizes the SRX state, and deoxy-ATP (dATP), a nucleotide that destabilizes SRX. In group 2, dATP augmented T max by 30% (p=0.0002) while M had no effect (p=0.1); meanwhile in group 1, M suppressed T max by 30% (p=0.0002) while dATP had no effect (p=0.9). Finally, a myosin activator EMD-57033, which increases probability of actin-myosin binding, augmented T max (correlation between ΔSRX-ΔT max r=-0.55, p=0.01). Conclusion: We find increased SRX myosin contributes to RV myofilament and chamber-level failure in PH-HF. Small molecules that recruit SRX myosin may have therapeutic benefit in patients with RV dysfunction.
Abstract 15142: Consistent Improvement in Utilization of Guideline Directed Medical Therapy Race for Traditionally Underserved Populations Using a Remote Intervention
Authors: Alexander J Blood, Joshua Bosque-Hamilton, Kavishwar Wagholikar, Lina Matta, David Zelle, Thomas A Gaziano, Jorge Plutzky, Benjamin M Scirica, Akshay S Desai
Journal: Circulation (2022)

Background: Heart failure (HF) disproportionately affects populations traditionally underserved in medicine. Remote healthcare delivery expands the reach of health care systems and providers, however some fear new models may pose challenges to equitable health care delivery. By building a remote HF clinic we aimed to increase equitable access to guideline-directed medical therapy (GDMT) optimization for HF. Methods: Patients with HF and a left ventricular ejection fraction &lt; 40% were identified by health record screening. Patients’ cardiologist was approached to participate in the remote intervention (RI) program, and those who declined their patient’s involvement served as a reference ‘usual care’ (UC) group. HF medications in the RI group were adjusted by pharmacists and patient navigators according to a GDMT titration algorithm. We examined differences in the efficacy of the intervention by race and separately by area deprivation index (ADI) - a validated method of stratifying neighborhood-level health determinants (higher scores indicate fewer resources). Results: Of 1131 eligible patients, 196 completed the 3-month follow-up in the RI group. The RI group included 16.8% Black individuals, 59.2% of patients in the low (1-5) ADI category and 29.6% in the high (6-10) ADI category. The UC group included 831 patients: 9.9% Black individuals, 54.0% in the low ADI category and 25.6% in the high ADI category. When compared to Black patients in UC, Black patients who participated in the RI program saw more medication titrations and rates of reaching target dosage for both ACE/ARB/ARNI &amp; beta-blockers (BB). When compared across ADI, the RI group had increased rates of ACE/ARB/ARNI &amp; BB titration and target dose achieved in the low and high ADI categories compared the UC group (Figure 1). Conclusion: A remote HF program was able to improve utilization of GDMT regardless of race and ADI. This care model may improve access to HF care for traditionally underserved populations.
Abstract 14905: A Combination of Polygenic Risk Scores for Coronary Artery Disease and for Circulating Blood Lipids Predicts the Incidence of Myocardial Infarction and Coronary Revascularization
Authors: Hasanga D Manikpurage, Zhonglin Li, Aida Eslami, Yohan Bosse, Patrick Mathieu, Benoit J Arsenault, Sebastien Theriault
Journal: Circulation (2022)

Introduction: Estimating the genetic risk of developing complex diseases, such as coronary artery disease (CAD), is now possible by aggregating data from genome-wide association studies (GWAS) into polygenic risk scores (PRS). This study aims to evaluate the performance of PRS derived from CAD (PRS CAD ) and blood lipids GWAS to predict severe CAD defined as myocardial infarction or coronary revascularization (MI-REVASC). Methods: Using nuclear magnetic resonance data from UK Biobank (UKB, n=90300), we conducted 29 GWAS for blood lipids (9 for fatty acids and 20 for lipoproteins). Summary statistics of these GWAS were then used to derive PRS in the rest of UKB (n=318422, median follow-up = 12.6 years). A PRS CAD was also calculated using the publicly available GWAS from the CARDIoGRAMplusC4D consortium. All PRS included &gt;1.1 million of genetic variants and were calculated using LDpred2. Hazard Ratio (HR) for incident MI-REVASC (n=10935) are reported with their 95% CIs, for 1-SD increase of each PRS. Selected independent PRS were combined into multivariate Cox regression models, for which predictive performance was evaluated. All models were adjusted for age, sex and genetic principal components. Results: Out of 30 PRS, 28 were significantly associated with incident MI-REVASC; PRS CAD showed the strongest association (HR=1.60 [1.57-1.63], p&lt;10e-300), whereas PRS for small LDL particles (sLDL-P) was the most associated blood lipids PRS (HR=1.14 [1.12-1.16], p=7.63e-42). The optimal model included PRS for CAD, sLDL-P, HDL-C and the PUFA/MUFA (poly-/mono- unsaturated fatty acids) ratio. Discriminative capacities for incident MI-REVASC were significantly increased in the model including PRS CAD (C-statistic (C) = 0.744 [0.739-0.748]) compared to the model without PRS (C= 0.710 [0.705-0.714]). No significant difference was observed when independent blood lipids PRS were added to the model (C= 0.745 [0.741 to 0.749]). Conclusions: Although independently associated with the incidence of severe CAD, blood lipids PRS provide little improvement in the predictive performance when added to PRS CAD .
Abstract 15059: Effects of Cigarette Smoke on Inflammation and Atrial Fibrillation
Authors: Padmini Sirish, Daphne Diloretto, Bob Kiaii, Nipavan Chiamvimonvat
Journal: Circulation (2022)

Introduction: Cigarette smoking is a major risk factor for occurrence and progression of several cardiovascular diseases. Smoking is associated with an increased risk of Atrial Fibrillation (AF). AF is an extremely common cardiac rhythm disorder that is associated with substantial morbidity and mortality. One of the main contributors for the initiation, progression and persistence of AF is inflammation. Cigarette smoke (CS) is known to increase inflammation. CS is known to increase pro-inflammatory cytokines and AF progression is associated with increased levels of these pro-inflammatory cytokines. Therefore, it is of great clinical importance to elucidate the underlying mechanisms contributing to smoking induced inflammation. The amplification of the pro-inflammatory cytokines is mediated by inflammasome and recently, the direct involvement of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain containing protein 3), inflammasome and AF has been demonstrated in patients with AF. The central hypothesis to be tested is that patients with AF and exposed to CS will demonstrate a heightened inflammation through the activation of NLRP3 inflammasome compared to patients in normal sinus rhythm (NSR) and non-smoking AF patients. Methods: Human atrial tissues and blood were obtained from patients undergoing coronary artery bypass graft surgery at UC Davis Medical Center in accordance with the approved UC Davis IRB protocol. An integrated approach using molecular biology, flow cytometry, and electrophysiology was used to test the components of NLRP3 inflammasome, inflammatory cytokines and structural remodeling in smoking and non-smoking AF and NSR patients using blood and human atrial tissue. Results: Our results demonstrate a significant increase in protein expression of component of the NLRP3 inflammasome including NLRP3, ASC and Caspase-1 in smoking AF and NSR patients compared to non-smoking patients. There was a significant increase in inflammatory cytokines activated by the NLRP3 inflammasome, IL-18 and IL-1β in in smoking AF and NSR patients compared to non-smoking patients. Conclusions: Our study not only provides important mechanistic insights into the roles of inflammasome in AF patients exposed to CS
Abstract 15015: Long Term Outcomes After Interrupted Aortic Arch Repair: A Study From the Pediatric Cardiac Care Consortium
Authors: Jamison C Miller, Romie Velani, Wade D Miller, Amanda S Thomas, Lazaros Kochilas
Journal: Circulation (2022)

Introduction: Interrupted aortic arch (IAA) is a congenital heart disease that can be successfully repaired. Children are at risk of multiple procedures and residual abnormalities. We used the Pediatric Cardiac Care Consortium (PCCC) to describe post-repair survival of patients with IAA. Methods: We queried the PCCC for patients receiving IAA repair 1982-2003. Death was ascertained from the PCCC and US National Death Index (NDI) to December 2019. Kaplan Meier (KM) plots and multivariable analysis assessed overall long-term survival and baseline characteristics associated with increased hazard of death post-repair. Results: We identified 380 patients (male 200; female 180) with IAA repair (excluding truncus arteriosus). Most had end-to-end anastomosis (n=234, 83.6%), 87 (31.1%) by interposition graft, and 47 (16.78%) by subclavian or carotid flap. There was no data for 11 patients. A total of 280 survived to discharge. Over a median of 22.9 years (IQR 19.78-27.52 years), 39 died. The 25-year survival post-discharge after repair was 86% (Figure 1). Type B2 IAA (aberrant right subclavian artery) was associated with increased death (aHR=1.814; 95% CI=0.891-3.694) versus non-type B IAA and cases with normal subclavians (A1+B1)) after adjusting for era, sex, presence of chromosomal anomalies, and type of surgery. Interposition graft was associated with increased hazard versus end-to end anastomosis (aHR=1.942; 95% CI=0.946-3.988) or vascular flaps (aHR=1.144; 95% CI=0.456-2.870). Other risk factors were female sex and chromosomal anomalies (DiGeorge syndrome primarily) (aHR = 1.948; 95% CI=0.946-4.011 and aHR=1.090; 95% CI=0.429-2.770). Conclusions: Patients with repaired IAA have decreased long-term survival. Female sex, chromosomal anomalies, type B IAA, aberrant right subclavian artery, and interposition graft were risk factors for poor long-term outcomes. Additional analysis of risk factors for long-term outcomes and causes of death is underway.
Abstract 15042: Cardiac-Enhanced Adeno-Associated Viral Vector Achieves Long-Term Transgene Expression in Transplanted Porcine Hearts When Administered During Ex Vivo Perfusion
Authors: Michelle Mendiola Pla, Yuting Chiang, Antonio Roki, Chunbo Wang, Franklin H Lee, Matthew F Smith, Ryan Gross, Amy Evans, Alexis Carnes, Desiree Bonadonna, Carolyn Glass, Muath Bishawi, Jacob N Schroder, Paul M Lezberg, Carmelo A Milano, Dawn E Bowles
Journal: Circulation (2022)

Introduction: Use of gene therapy for cardiac transplantation is limited by the lack of an effective recombinant Adeno-associated viral vector (rAAV) gene delivery strategy. Ex vivo normothermic perfusion has been increasingly used in clinical practice and is an effective platform for achieving robust global gene delivery to a donor heart. Here we utilized a rationally designed cardiac-enhanced AAV3b variant, SASTG, to deliver the gene firefly luciferase to porcine hearts and evaluated transgene expression 30-days post-transplantation. Methods: Heterotopic heart transplantation was performed using blood-type and MHC matched Yucatan pigs (n=4). Donor hearts underwent ex vivo perfusion for 2-hours with perfusate containing the rAAV SASTG-Luciferase. Three different doses of rAAV were used: 2x10 13 , 8x10 13 , 1x10 14 viral genome copies (VGC). Recipients were survived for 30 days at which time they were euthanized and donor and recipient hearts were examined for overall levels of luciferase activity, luciferase DNA copy number, and histology for luciferase expression on immunostaining and evidence of inflammation. Results: There was a dose-dependent response in luciferase activity observed in the donor heart ventricles with the lowest activity detected at the 2x10 13 VGC dose (1.5-9.9x10 3 RLU/mg) mid-level activity at the 8x10 13 VGC dose (32.7-71.2x10 3 RLU/mg) and highest activity at the 1x10 14 VGC dose (27.6-278.1x10 3 RLU/mg). Luciferase DNA was detectable in a dose-dependent manner in the donor heart ventricles (0.02-131.1x10 3 VGC/pg of DNA), but undetectable in all native hearts. Finally, immunostaining demonstrated diffuse luciferase expression in the donor heart but none in the recipient hearts. There was also no evidence of inflammation in any of the donor hearts. Conclusions: The cardiac-enhanced AAV3b variant, SASTG, is associated with robust, global transgene expression in porcine cardiac allografts when administered during ex vivo perfusion.
Abstract 14821: Effect of Single Volatile Organic Compound Metabolites and Volatile Organic Compound Mixtures on Vascular Function
Authors: Cameron Stopforth, Clara Sears, Justin Dials, Sanjay Srivastava, Aruni Bhatnagar, Rachel J Keith
Journal: Circulation (2022)

Volatile organic compounds (VOCs) are ubiquitous environmental toxicants with pre-clinical evidence of decreased vascular health. Research to date has focused on single VOC metabolites and data is lacking on the effects on human vascular health. Many VOCs are strongly correlated with similar exposure sources. Though the compounding effects are poorly defined, they are likely to increase the overall toxicity. Therefore, we examined single VOC metabolites and mixtures’ association with flow mediated dilation (FMD), an index of vascular health. We recruited adult participants into a CV risk cohort, aged 25-70 years, from 2018 and 2019. A panel of urinary VOC metabolites were measured in 308 non-smoking participants who had completed brachial artery FMD. Regression analysis of 16 VOC analytes was tested for associations with %FMD and models were adjusted for covariates selected a priori including age, sex, diabetes and ACE inhibitors. We examined the joint effect of MU, 3HPMA, CEMA, CYMA, DHBMA, 2HPMA, 2MHA, and AAMA mixtures on log-transformed %FMD using quantile-based g-computation models adjusted for the covariates above and for correlated VOC metabolites that were not associated with FMD in single metabolite analyses. The mean %FMD was 7.1 % ± 4.7%. VOC metabolites that were predictors of decreased %FMD in fully adjusted models were 3HPMA (β=-1.275; 95% CI= -2.402, -0.148; p=0.027), CEMA (β= -1.204; 95% CI= -2.051; -0.357 p=0.006), AAMA (β=-1.125; 95% CI= -2.156, -0.094; p=0.033), 2HPMA (β= -1.035; 95% CI= -1.847, -0.222 p=0.013), and 2MHA (β=-0.623; 95% CI= -1.123, -0.124; p=0.015). Most VOC metabolites had fair to moderate correlations in bivariate analyses (Spearman correlation from 0.06 to 0.60). We found that a quartile increase in the VOC mixture was associated with 20% lower percent FMD (ψ -0.18; 95%CI= -0.35, -0.02; p=0.027) in adjusted models. We found the overall mixture effect was driven primarily by 3HPMA, followed by CYMA, CEMA, 2MHA, and AAMA. Therefore, the main driver of the association between the VOC mixture and decreased vascular function is acrolein and to a lesser extent acrylonitrile. Future research could focus on identifying sources of exposure to these VOCs to promote better vascular health among non-smokers.
Abstract 14860: Quantitative Whole Blood Platelet Aggregation Predicts Occurrence of Subacute Thrombosis in Patients After Percutaneous Coronary Intervention
Authors: Nobusada Funabashi, Shin Akaza, Kohki Nakamura, Kazuo Misumi
Journal: Circulation (2022)

Introduction: The risk of subacute thrombosis (SAT) after percutaneous coronary intervention (PCI) is high if patients show high whole blood platelet aggregation. Hypothesis: For such high-risk patients, even though dual antiplatelet therapy is performed, whole platelet aggregation should be quantitated and if high, the indication for additional antiplatelet therapy determined. Methods: This is a retrospective analysis of 26,314 stents from 26,314 patients (20,028 males; mean age 70±11 years). The whole blood platelet aggregatory threshold index (PATI; WBA-Neo; ISK, Osaka, Japan) was calculated. PATI was used to determine the minimum concentration of adenosine 5'-diphosphate causing a non-reversible aggregation of platelets and indicated platelet aggregation (range 0-8 μM). The higher the PATI, the lower the platelet aggregation. All patients received single or double antiplatelet drug therapy according to physician choice. Results: SAT occurred in 35 (0.13%) of 26,314 patients after PCI. Total blood PATI was 5.25±2.46 in 35 patients with SAT and 7.14±1.75 in 26,279 patients without SAT (P&lt;0.001). Receiver operating characteristic (ROC) curves of the PATI for detection of occurrence of SAT showed an area under the curve (AUC) of 0.721. Best cutoff point of PATI was 6.435μM (sensitivity of 81% and specificity of 66%) for detection of occurrence of SAT (Youden index=0.464, P&lt;0.001). No significant differences existed in the percentage of each coronary risk factor between patients with and without SAT after PCI (63% vs 47% for diabetes mellitus, P=0.054, 66% vs 75% for hypertension, P=0.209, 46% vs 57% for hyperlipidemia, P=0.190, and 34% vs 28% for smoking habits, P=0.381). Conclusions: In patients after PCI, despite single or double antiplatelet drug therapy, the whole blood platelet aggregation should be checked, and if PATI is &lt;6.435 the indication for additional antiplatelet therapy should be considered.